The Genetics of Obsessive Compulsive Disorder and Related OCD Spectrum Disorders

强迫症和相关强迫症谱系障碍的遗传学

• 批准号: 8745669
• 负责人: DENNIS L MURPHY
• 金额: $ 75.37万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745669
• 关键词: 9p24; Adult; Adverse drug effect; Affect; Affective; Animal Model; Annual Reports; Anxiety; Anxiety Disorders; Autistic Disorder; Bipolar Disorder; Brain; Brain imaging; Brain region; Candidate Disease Gene; Case-Control Studies; Cluster Analysis; Code; Collection; Complex; Corpus striatum structure; DNA; DSM-IV; Data; Databases; Development; Diagnostic; Diagnostic and Statistical Manual; Disease; Excitatory Amino Acid Antagonists; Extramural Activities; Factor Analysis; Family Study; Family member; Fluoxetine; Foundations; Future; Gene Expression; General Hospitals; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Gilles de la Tourette syndrome; Glutamate Transporter; Glutamates; Goals; Homeobox Genes; Human; Human Cell Line; Individual; Investigation; Laboratories; Life Stress; Manuscripts; Maps; Massachusetts; Medical; Mental Depression; Mining; Modeling; Molecular Genetics; Monobactams; Mood Disorders; Mus; Neurons; Neurotransmitters; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Paper; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Play; Population; Prevalence; Prosencephalon; Proteins; Protocols documentation; Public Health; Publications; Publishing; Reporter Genes; Reporting; Riluzole; Role; Schizophrenia; Series; Serotonin; Serotonin Syndrome; Siblings; Signal Transduction; Site; Susceptibility Gene; Synapses; System; Techniques; Transgenic Organisms; Variant; Work; World Health Organization; base; brain tissue; case control; density; disability; disorder subtype; extracellular; gene environment interaction; genetic linkage analysis; genetic variant; genome wide association study; genome-wide; high risk; human disease; improved; insight; knowledge base; meetings; neurodevelopment; neuropsychiatry; neurotropic; overexpression; proband; response; reuptake; trait; treatment response

OCD is a severe, heritable condition with a lifetime prevalence of about two percent in world populations. First-degree family members and OCD probands are at a ten-fold higher risk of developing OCD and related disorders. The mode of inheritance is incompletely understood but is likely complex, involving multiple genetic loci of small to moderate effect. Our laboratory has played a leading role in studies of OCD and of its genetics for over 25 years, and was one of the founding sites of multi-center genome-wide project for studies of OCD, partial results of which have recently been reported in the group's publications noted below. In addition, a series of association studies that has identified and evaluated several genes in OCD and related disorders is continuing. In our Lab's collaborative investigations, we have also worked to clarify the fundamental phenotypical features of OCD and related disorders, sometimes designated 'OCD spectrum disorders', in reports published in 2012-2013. We currently have a multifaceted array of compulsive phenotypical features that cut across traditional diagnostic designations (DSM-IV and DSM-5). In continuing efforts, our group and our collaborators have been using latent class modeling to go beyond factor and cluster analyses in order to parse OCD and related disorders by considering underlying features and comorbid disorders (e.g., affective/bipolar disorders) and life stresses. Examples of some sub-disorders that can contribute to OCD but can be found without classic OCD features include our recent and prior studies of Tourette's disorder and hoarding as well as of comorbid affective disorders, including bipolar disorder. Bipolar disorder is also the subject of direct and molecular genetic studies in continuing collaborative investigations with the Bipolar Genetics Consortium group. Studies are ongoing of the role of serotonin, the SLC6A4 gene and other major serotonin genes plus SLC1A1 in OCD and related disorders such as Tourette disorder (in which 50% of patients meet diagnostic criteria for OCD). A manuscript was published this year about the multiple common and rare SLC6A4 variants found to be associated with Tourette's Disorder including the 5HTTLPR, rs25531, rs25532 and SERT I425V variants (Moya et al., 2013). The relationship of SLC6A4 variants to different SRI treatment responses in humans represents an additional illustration of gene-based influences on serotonergic pharmacologic responses, i.e., a new SERT-based pharmacogenomics, directly relevant to the treatment of human neuropsychiatric disorders such as OCD and depression as well as to other serotonin-related human diseases as we have recently reviewed. Recent evidence from treatment and genetic studies suggest that another neurotransmitter system may contribute to OCD. As with SERT in the serotonin system, the neuronal glutamate transporter is a major regulator of glutamate availability. This glutamate transporter, EAAC3, is encoded by the gene SLC1A1 located within the chromosomal region 9p24. Recent evidence from 9p24 gene linkage analyses and candidate gene studies has suggested probable involvement of SLC1A1 in the development of OCD. Our large case-control study of SLC1A1 included a total of over 950 OCD probands and controls collected by our Lab were published this year. In addition, SLC1A1 expression and data were recently evaluated to gain further insights into SLC1A1 function. We found that gene expression of SLC1A1 is heritable in human cell lines. We identified three SNPs in or near SLC1A1 that correlated with gene expression levels. Additionally, two of these SNPs also predicted expression levels in human post-mortem brain tissue, and one SNP was found to have functional consequences in reporter gene studies. We are currently continuing further lab-based studies of this gene using transgenic techniques in mice and Dr. Moya from our Lab has created conditional Slc1a1 mice, one set of which has this gene deleted and another set which preferentially overexpresses this gene in the forebrain. The rational for creating these two opposite functional Slc1a1 mice was based on the equivocal findings from the human SLC1A1 studies regarding whether this gene might be hypofunctional or hyperfunctional in OCD. These investigations, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and database-mining approach that we used provides a new and useful complementary model approach to strengthen future GWAS and candidate rare functional gene studies in neuropsychiatric and other disorders which represent a large public health burden. In fact, seven neuropsychiatric disorders, including OCD, were listed in the 2001 World Health Organizations report as among the leading causes of years of extended disability among adults. Thus these studies are expected to have a considerable public health impact. In additional studies of the genetics of OCD, we focused on candidate genes for OCD based on animal models of some OCD-related compulsive behaviors. These studies thus bring an even sharper focus on OCD subtypes or sub-populations that may be more closely related to specific single genes. Also of note is that our group continues to share our 25+ year collection of DNA and phenotype data with collaborators in the Obsessive-Compulsive Disorder Collaborative Genetics Study (OCGS) and the Obsessive-Compulsive Foundation (OCF) groups, as well as with other intramural and extramural individual collaborators, thus enhancing the global search for underlying contributions to OCD and related disorders that are of major public health concerns. Many papers that were published in the last year that are listed below resulted from these collaborative studies. The collaborative study to which our Lab contributed DNA and phenotype data based at Massachusetts General Hospital yielded a case-control genome association study involving 7022 individuals published in 2012. One of the top signals obtained was in DLGAP1, coding a post-synaptic density (PSD) protein with high similarity to another PSD gene, DLGAP3 (SAPAP3) which we found to have rare variants enriched in OCD patients versus controls, as reported in a 2011 paper from our group and colleagues. The OCF collaborational GWAS was conceived to compliment the earlier OCGS family-based genome linkage study of 299 OCD-affected sibling pairs together with other family members and now constitutes more than 1100 individuals. The OCGS studies generated 20 publications to date, the most recent last year. This study conducted fine mapping followed by SNP association studies of two regions identified in the initial linkage analysis. Associations were identified in or near a set of associated homeobox genes including MEIS2. Two of these form a heterodemeric complex. All three are involved in neurodevelopment and the heterodemeric complex is specifically known to affect development of the striatum, a brain region previously implicated in OCD via human brain imaging studies. Citations numbers of other papers that have referenced our scientific reports number over 35,000 as of August, 2013. The protocol number for this Annual Report is 96-M-0124 and the NCT number is NCT00001548.

强迫症是一种严重的遗传性疾病，世界人口的终生患病率约为百分之二。一级家庭成员和强迫症先证者患强迫症和相关疾病的风险高出十倍。遗传模式尚不完全清楚，但可能很复杂，涉及多个小到中等影响的遗传位点。我们的实验室在强迫症及其遗传学研究中发挥了主导作用超过 25 年，并且是强迫症研究多中心全基因组项目的创始地点之一，该项目的部分结果最近在该小组的出版物中报道如下。此外，一系列已识别和评估强迫症及相关疾病中的几个基因的关联研究仍在继续。 在我们实验室的合作研究中，我们还努力在 2012-2013 年发表的报告中阐明强迫症和相关疾病（有时称为“强迫症谱系障碍”）的基本表型特征。目前，我们拥有一系列跨越传统诊断名称（DSM-IV 和 DSM-5）的强迫性表型特征。在不断的努力中，我们的小组和我们的合作者一直在使用潜在类别模型来超越因素和聚类分析，以便通过考虑潜在特征和共病障碍（例如情感/双相情感障碍）和生活压力来解析强迫症和相关疾病。一些可能导致强迫症但没有典型强迫症特征的亚疾病的例子包括我们最近和之前对抽动秽语症和囤积症以及共病情感障碍（包括双相情感障碍）的研究。双相情感障碍也是双相情感障碍遗传学联盟小组持续合作研究中直接和分子遗传学研究的主题。 血清素、SLC6A4 基因和其他主要血清素基因加上 SLC1A1 在强迫症和抽动秽语症等相关疾病（其中 50% 的患者符合强迫症的诊断标准）中的作用的研究正在进行中。今年发表了一份手稿，涉及与图雷特氏症相关的多种常见和罕见 SLC6A4 变体，包括 5HTTLPR、rs25531、rs25532 和 SERT I425V 变体（Moya 等人，2013）。 SLC6A4 变体与人类不同 SRI 治疗反应的关系进一步说明了基因对血清素药理反应的影响，即一种新的基于 SERT 的药物基因组学，与人类神经精神疾病（如强迫症和抑郁症）以及我们最近综述的其他与血清素相关的人类疾病的治疗直接相关。 最近的治疗和遗传学研究证据表明，另一种神经递质系统可能导致强迫症。与血清素系统中的 SERT 一样，神经元谷氨酸转运蛋白是谷氨酸可用性的主要调节因子。这种谷氨酸转运蛋白 EAAC3 由位于染色体区域 9p24 内的基因 SLC1A1 编码。最近来自 9p24 基因连锁分析和候选基因研究的证据表明 SLC1A1 可能参与强迫症的发展。 我们对 SLC1A1 的大型病例对照研究包括我们实验室收集的总共 950 多名强迫症先证者和对照，该研究已于今年发表。此外，最近评估了 SLC1A1 表达和数据，以进一步了解 SLC1A1 功能。我们发现 SLC1A1 的基因表达在人类细胞系中是可遗传的。我们在 SLC1A1 中或附近发现了三个与基因表达水平相关的 SNP。此外，其中两个 SNP 还预测了人类死后脑组织中的表达水平，并且发现一个 SNP 在报告基因研究中具有功能性影响。目前，我们正在继续利用小鼠转基因技术对该基因进行进一步的实验室研究，我们实验室的 Moya 博士已经创建了条件性 Slc1a1 小鼠，其中一组删除了该基因，另一组优先在前脑过度表达该基因。创造这两只功能相反的 Slc1a1 小鼠的理由是基于人类 SLC1A1 研究的模棱两可的发现，即该基因在强迫症中是否功能低下或功能亢进。这些研究综合起来表明，SLC1A1 与 SLC6A4 一样，是强迫症的易感基因。我们使用的表达和数据库挖掘方法提供了一种新的、有用的补充模型方法，以加强未来的 GWAS 和候选稀有功能基因在神经精神疾病和其他代表巨大公共卫生负担的疾病中的研究。事实上，2001 年世界卫生组织报告将包括强迫症在内的七种神经精神疾病列为导致成年人长期残疾的主要原因之一。 因此，这些研究预计将对公共健康产生相当大的影响。 在强迫症遗传学的其他研究中，我们根据一些强迫症相关强迫行为的动物模型，重点关注强迫症的候选基因。因此，这些研究更加关注可能与特定单基因更密切相关的强迫症亚型或亚群。 另外值得注意的是，我们的小组继续与强迫症协作遗传学研究 (OCGS) 和强迫症基金会 (OCF) 小组的合作者以及其他校内和校外个人合作者分享我们 25 多年收集的 DNA 和表型数据，从而加强了全球对强迫症和相关疾病的潜在贡献的搜索，这些疾病是主要的公共卫生问题。下面列出的去年发表的许多论文都是这些合作研究的结果。 我们的实验室在马萨诸塞州总医院提供 DNA 和表型数据的合作研究产生了一项涉及 7022 名个体的病例对照基因组关联研究，该研究于 2012 年发表。获得的最重要信号之一是 DLGAP1，编码一种突触后密度 (PSD) 蛋白，与另一个 PSD 基因 DLGAP3 (SAPAP3) 高度相似，我们发现该基因富含罕见变体 正如我们小组和同事在 2011 年发表的一篇论文中所报道的那样，强迫症患者与对照组之间的差异。 OCF 合作 GWAS 旨在补充早期基于 OCGS 家庭的基因组连锁研究，该研究涉及 299 对受强迫症影响的兄弟姐妹以及其他家庭成员，现在已超过 1100 人。 OCGS 研究迄今为止已发表 20 篇出版物，最近的一次是去年的。这项研究进行了精细绘图，随后对初始连锁分析中确定的两个区域进行了 SNP 关联研究。在一组相关的同源盒基因（包括 MEIS2）中或附近发现了关联。其中两个形成异源复合物。这三者都与神经发育有关，并且已知异源复合物会影响纹状体的发育，纹状体是先前通过人脑成像研究发现与强迫症有关的大脑区域。 截至 2013 年 8 月，引用我们科学报告的其他论文的引用次数已超过 35,000 次。 本年度报告的协议号为 96-M-0124，NCT 号为 NCT00001548。